1. Field of the Invention
The present invention relates to the semi-synthesis of taxane intermediates and aziridine analogues, in particular, aziridine analogues of cephalomannine and baccatin III intermediates, and their conversion to active antitumor agents, paclitaxel and docetaxel.
2. Description of the Prior Art
Docetaxel (1, Taxotere), a semi-synthetic analog, and paclitaxel (2, Taxol), a complex diterpene isolated from the bark of the Pacific yew tree (Taxus brevifolia) are arguably the most outstanding cancer chemotherapeutic substances discovered in recent times. While paclitaxel can be obtained from the yew tree or semi-synthetically, only the latter option is currently available for the formation of non-natural docetaxel. The partial synthesis of this important compound has generally been accomplished through esterification of a derivative of the (2R, 3S) phenylisoserine side chain with a protected form of 10-deacetylbaccatin III, a comparatively abundant natural product also present in the yew tree.
In Colin's U.S. Pat. No. 4,814,470, it was reported that docetaxel has an activity significantly greater than paclitaxel.
Docetaxel and paclitaxel may be prepared semi-synthetically from 10-deacetylbaccatin III or baccatin III as set forth in U.S. Pat. Nos. 4,924,011 and 4,924,012 or by the reaction of a β-lactam and a suitably protected 10-deacetylbaccatin III or baccatin III derivative as set forth in U.S. Pat. No. 5,175,315. 10-deacetylbaccatin III (10-DAB, 3) and Baccatin III (4) can be separated from mixtures extracted from natural sources such as the needles, stems, bark or heartwood of numerous Taxus species and have the following structures.

Although, most of the research towards the semi-synthesis of docetaxel and paclitaxel has involved 10-deacetylbaccatin III as the starting material, other taxanes present in the yew tree, such as 9-dihydro-13-acetylbaccatin III (9DHB, 5), present in the Canadian yew (Taxus Canadensis), and cephalomannine (6) have been collected and identified.

As disclosed in U.S. patent application Ser. No. 10/695,416, which application is assigned to the assignee of the present invention, docetaxel and pacliaxel may also be prepared semi-synthetically from 9-dihydro-13-acetylbaccatin III.
Although there have been many advances in the field, there remains a need for new and improved processes for the preparation of taxane intermediates and their conversion to docetaxel and paclitaxel. The present invention addresses these needs and provides further related advantages.